Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The synthesis of water-soluble, unsymmetrical, trisulfonated zinc phthalocyanines (ZnPcS3) as single products of the ring expansion of boron tri(4-sulfo)subphthalocyanine (SubPc) is reported. The novel, water-soluble trisulfo-SubPcB(OH) was prepared via hydrolysis of the tris(4-chlorosulfonyl)SubPcB(Br) which in turn was obtained from the condensation of 4-(chlorosulfonyl)phthalonitrile with BBr3 in 1-chlorobenzene. A number of ZnPcS3 analogues were prepared via the reaction of S3SubPcB (OH) with different diiminoisoindoline derivatives of increasing hydrophobicity. The reaction proceeds at relative low temperature with acceptable yields. Metalation of free base Pc's with zinc acetate dihydrate afforded the corresponding zinc complexes. Photodynamic activities were measured against the EMT-6 mouse mammary tumor cell line and compared to those of the known ZnPcS3 and ZnPcS4. Added (t-Bu)benzo and (t-Bu)naphtho groups increased the in vitro cell photoinactivation efficacy of the ZnPcS3, whereas addition of a fourth sulfobenzo or bulky diphenylpyrazino group decreased the activity of the parent molecule. The (t-Bu)naphthotrisulfobenzoporphyrazine induced the best in vivo photodynamic tumor control which, combined with its good solubility and broad absorption spectrum, renders this compound an interesting dye for photodynamic applications in medicine.
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PMID:Syntheses and photodynamic activities of novel trisulfonated zinc phthalocyanine derivatives. 939 70

The first control of a malignant tumor in vivo by porphyrin- mediated boron neutron capture therapy (BNCT) is described. In mice bearing implanted EMT-6 mammary carcinomas, boron uptake using a single injection of either p-boronophenylalanine (BPA) or mercaptoundecahydrododecaborane (BSH) was compared with either a single injection or multiple injections of the carboranylporphyrin CuTCPH. The BSH and BPA doses used were comparable to the highest doses of these compounds previously administered in a single injection to rodents. For BNCT, boron concentrations averaged 85 microg (10)B/g in the tumor and 4 microg (10)B/g in blood 2 days after the last of six injections (over 32 h) that delivered a total of 190 microg CuTCPH/g body weight. During a single 15, 20, 25 or 30 MW-min exposure to the thermalized neutron beam of the Brookhaven Medical Research Reactor, a tumor received average absorbed doses of approximately 39, 52, 66 or 79 Gy, respectively. A long-term (>200 days) tumor control rate of 71% was achieved at a dose of 66 Gy with minimal damage to the leg. Equivalent long-term tumor control by a single exposure to 42 Gy X rays was achieved, but with greater damage to the irradiated leg.
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PMID:Boron neutron capture therapy of a murine mammary carcinoma using a lipophilic carboranyltetraphenylporphyrin. 1126 Jun 62

The biodistributions of carborane-containing copper porphyrins, CuTCP and CuTCPH, have been studied previously in mice bearing subcutaneously implanted mammary carcinomas. We now report biodistributions of those porphyrins in Fischer 344 rats bearing intracranial and/or multiple subcutaneous isogeneic 9L gliosarcomas (9LGS). The porphyrin was given either by i.v. infusion or by multiple i.p. injections. When 190 mg CuTCPH/kg body weight was given to the rats by i.v. infusion, median tissue boron concentrations (microg/g) 3 days after the end of infusion were: 64 in subcutaneous tumor, 13 in intracranial tumor, 1 in blood and 3 in brain. When 450 mg CuTCPH/kg body weight was given to the rats by serial i.p. injections, the median concentrations (microg B/g) 4 days after the last injection were: 117 in subcutaneous tumor, 50 in intracranial tumor, 4 in blood, and 4 in brain. CuTCPH biodistribution was also studied in xenografts of the human malignant gliomas U87 and U373, and of the murine EMT-6 mammary carcinoma and the rat 9LGS, each grown subcutaneously in mice with severe combined immunodeficiency (SCIDs). In SCIDs, median boron concentrations (microg/g) 2 days after the last s.c. injection of a total of 190 mg CuTCPH/kg body weight were: 251 in U373, 33 in U87, <0.6 in blood and <0.5 in brain. Because there were such high boron levels in the U373, and because xenografted U373 is similar to spontaneous intracerebral human glioblastoma multiforme (GBM) microscopically, CuTCPH could prove useful as a boron carrier for boron neutron-capture therapy (BNCT) of GBM and of other human malignant gliomas.
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PMID:Biodistribution of copper carboranyltetraphenylporphyrins in rodents bearing an isogeneic or human neoplasm. 1150 10

Kaposi's sarcoma (KS) is the most common tumor affecting AIDS patients with over 20% of these patients afflicted by this disease. Previous studies have demonstrated that KS tumor cells predominantly express the prosurvival protein Bcl-X(L) compared with Bcl-2. In the current study, we have used an adenoviral vector that expresses Bcl-X(S), a functional inhibitor of Bcl-X(L), to study the significance of Bcl-X(L) expression in the KS cell line (SLK) or KS primary cultures. The results demonstrate that 75% to 80% of SLK or KS primary cells were killed by the Bcl-X(S) containing adenovirus whereas KS cells infected with control adenovirus showed no significant cell death or growth inhibition. Overexpression of Bcl-X(L), but not Bcl-2, in SLK cells attenuated apoptosis induced by adenovirus Bcl-X(S). Immunoprecipitation experiments revealed that adenoviral Bcl-X(S) associated with Bcl-X(L), but not with Bcl-2. Mutational analysis showed that the alpha 2 helical region of Bcl-X(S) containing the BH3 motif was critical for killing activity and interaction with Bcl-X(L). These results suggest that Bcl-X(S) is a direct killer and Bcl-X(L) may act by interacting with and sequestering Bcl-X(S.) These studies also suggest that targeting Bcl-X(L) may be of therapeutic benefit for the treatment of tumors that are characterized by inappropriate expression of Bcl-X(L).
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PMID:Killing of sarcoma cells by proapoptotic Bcl-X(S): role of the BH3 domain and regulation by Bcl-X(L). 1168 55

CC139 fibroblasts are one of several model systems in which the Raf --> MEK --> ERK1/2 pathway can inhibit apoptosis independently of the PI3K pathway; however, the precise mechanism for this protective effect is not known. Serum withdrawal from CC139 fibroblasts resulted in the rapid onset of apoptosis, which was prevented by actinomycin D or cycloheximide. Serum withdrawal promoted the rapid, de novo accumulation of Bim(EL), a proapoptotic 'BH3-only' member of the Bcl-2 protein family. Bim(EL) expression was an early event, occurring several hours prior to caspase activation. In contrast to studies in neurons, activation of the JNK --> c-Jun pathway was neither necessary nor sufficient to induce Bim(EL) expression. Selective inhibition of either the ERK pathway (with U0126) or the PI3K pathway (with LY294002) caused an increase in the expression of Bim(EL). Furthermore, selective activation of the ERK1/2 pathway by deltaRaf-1:ER* substantially reduced Bim(EL) expression, abolished conformational changes in Bax and blocked the appearance of apoptotic cells. The ability of deltaRaf-1:ER* to repress Bim(EL) expression required the ERK pathway but was independent of the PI3K --> PDK --> PKB pathway. Thus, serum withdrawal-induced expression of Bim(EL) occurs independently of the JNK --> c-Jun pathway and can be repressed by the ERK pathway independently of the PI3K pathway. This may contribute to Raf- and Ras-induced cell survival at low serum concentrations.
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PMID:Activation of ERK1/2 by deltaRaf-1:ER* represses Bim expression independently of the JNK or PI3K pathways. 1261 53

Boron isotopes are potentially very important to cosmochemistry, geochemistry, and paleoceanography. However, the application has been hampered by the large sample required for positive thermal ionization mass spectrometry (PTIMS), and high mass fractionation for negative-TIMS (NTIMS). Running as BO(2)(-), NTIMS is very sensitive and requires only nanogram sized samples, but it has rather poor precision (approximately 0.7-2.0 per thousand) as a result of the larger mass fractionation associated with the relatively light ion. In contrast, running as the much heavier molecule of Cs(2)BO(2)(+), PTIMS usually achieves better precision around 0.1-0.4 per thousand. Moreover, there is a consistent 10 per thousand offset in the (11)B/(10)B ratio for NIST SRM 951 standard boric acid between the NTIMS and the certified value, but the cause of this offset is unclear. In this paper, we have adapted a technique we developed earlier to measure the (138)La/(139)La using LaO(+) (1) to improve the NTIMS technique for BO(2). We were able to correct for instrumental fractionation by measuring BO(2)(-) species not only at masses of 42 and 43, but also at 45, which enabled us to normalize (45)BO(2)/(43)BO(2) to an empirical (18)O/(16)O value. We found that both I(45)/I(42) = ((11)B(16)O(18)O/(10)B(16)O(16)O) and (I(43)/I(42))(C) = ((11)B(16)O(16)O/(10)B(16)O(16)O) vary linearly with (I(45)/I(43))(C) x 0.5 = ((11)B(16)O(18)O/(11)B(16)O(16)O) x 0.5 = (18)O/(16)O. In addition, different activators and different chemical forms of B yield different slopes for the fractionation lines. After normalizing (11)B(16)O(18)O/(11)B(16)O(16)O x 0.5 to a fixed (18)O/(16)O value, we obtained a mean (11)B/(10)B value of NIST SRM 951 that matches the NIST certified value at 4.0430 +/- 0.0015 (+/-0.36 per thousand, n = 11). As a result, our technique can achieve precision and accuracy comparable to that of PTIMS with only 1 per thousand of the sample required. This new NTIMS technique for B isotopes is critical to the studies of early solids in the solar system and individual foraminifera in sediments that require both high sensitivity and precision.
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PMID:A 10-fold improvement in the precision of boron isotopic analysis by negative thermal ionization mass spectrometry. 1272 Mar 29

The total synthesis of a 5,15-di[3,5-(o-carboranylmethyl)phenyl]porphyrin 5, its zinc(II) complex 6, and the corresponding nido-carboranylporphyrins 7 and 8 are reported. The molecular structures of porphyrin 6 and of potassium nido-carborane were obtained and are described. The biodistribution of nido-carboranylporphyrins 7 and 8 in BALB/c mice bearing EMT-6 mammary tumors are presented and compared. Both compounds are effective tumor localizers and delivered therapeutic concentrations of boron to tumors (mean+/-standard deviation): 32.5+/-7.1 and 54.3+/-14 microg/g for 7 and 8, respectively, 2 days after the last of 3 injections of a total boron dose of 23 mg/kg body weight. The zinc(II) complex 8 was found to deliver 1.2-1.7 times higher amounts of boron to tumors than 7, with lower tumor-to-blood boron concentration ratios (9.8/1 and 4.7/1 for 7 and 8, respectively, 2 days after injections). The tumor-to-brain boron concentration ratios were >100/1 for both porphyrins 2 days after administration. Both nido-carboranylporphyrins 7 and 8 were well-tolerated at the concentrations used (75 and 78 mg/kg body weight, respectively) and no morbidity or mortality were observed in these studies.
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PMID:Synthesis, toxicity and biodistribution of two 5,15-di[3,5-(nido-carboranylmethyl)phenyl]porphyrins in EMT-6 tumor bearing mice. 1281 72

A technique for precise boron isotope ratio measurements with a high detection power has been developed by negative thermal ionization mass spectrometry (NTIMS). Relative standard deviations in the range of 0.03-0.3% have been obtained for the determination of the (11)B/(10)B isotope ratio using nanogram amounts of boron. Ba(OH)(2) has been applied as ionization promoter for the formation of negative thermal ions. By adding MgCl(2) better reproducibilities of the measurement have been achieved. A possible interference of BO(-)(2) ions at mass number 42 by CNO(-) could be excluded by the sample preparation technique used. Contrary to other NTI techniques no dependence of the measured isotope ratio on the boron amount used has been observed. Anthropogenic and natural saline influences in ground water have been successfully identified by boron isotope ratio determinations with this NTIMS method, due to the different isotopic composition of boron in natural and anthropogenic substances. In sewage, the boron isotope ratio is substantially influenced by washing powder, which contains low (11)B/(10)B ratios (expressed in delta(11)B values normalized to the standard reference material NIST SRM 951). In contaminated ground water, low delta(11)B values are normally correlated with high boron and high chloride concentrations. On the other hand, delta(11)B shifts to higher values in less contaminated samples. For ground water with saline influences, only the delta(11)B determination, and not the boron or chloride content, allowed the correct identification of this natural source of contamination.
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PMID:Determination of boron isotopic variations in aquatic systems with negative thermal ionization mass spectrometry as a tracer for anthropogenic influences. 1504 14

Copper tetracarboranyltetraphenylporphyrin (CuTCPH) is a minimally toxic carborane-containing porphyrin that has safely delivered high concentrations of boron for experimental boron neutron capture therapy (BNCT). Copper octabromotetracarboranylphenylporphyrin (CuTCPBr), synthesized by bromination of CuTCPH, is one of several new minimally toxic analogues of CuTCPH being studied in our laboratory, which could possess comparable or better tumour-targeting properties with enhanced tumour cytotoxicity. Its biodistribution, biokinetics and toxicity in mice with subcutaneous EMT-6 (mammary) or SCCVII (squamous cell) carcinomas were compared with those of CuTCPH. The administration of approximately 200 mg kg(-1) of either porphyrin in six intraperitoneal injections over 2 days had no apparent effect, but administration of approximately 400 mg kg(-1) slightly lowered body weights, elevated alanine and aspartate transaminase activities in blood plasma, and depressed blood platelet counts for several days. Enzymes and platelets returned to normal within 5 days after those injections and body weights returned to normal within 2 weeks. High average concentrations of boron from either porphyrin were achieved in the two tumour models from a total dose of approximately 200 mg kg(-1). The high tumour boron concentration decreased slowly while concentrations in blood decreased rapidly. Boron concentrations in brain and skin were consistently lower than in tumour by a factor of 10 or more. Although either CuTCPH or CuTCPBr can be labelled with (64)Cu for imaging by positron emission tomography (PET), CuTCPBr can also be labelled by (76)Br, another PET-imageable nuclide.
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PMID:Synthesis of copper octabromotetracarboranylphenylporphyrin for boron neutron capture therapy and its toxicity and biodistribution in tumour-bearing mice. 1523 4

An instrument for cold neutron prompt gamma-ray activation analysis (PGAA), located at the NIST Center for Neutron Research (NCNR), has proven useful for the measurement of boron in a variety of materials. Neutrons, moderated by passage through liquid hydrogen at 20 K, pass through a (58)Ni coated guide to the PGAA station in the cold neutron guide hall of the NCNR. The thermal equivalent neutron fluence rate at the sample position is 9 x 10(8) cm(-2) s(-1). Prompt gamma rays are measured by a cadmium- and lead-shielded high-purity germanium detector. The instrument has been used to measure boron mass fractions in minerals, in NIST SRM 2175 (Refractory Alloy MP-35-N) for certification of boron, and most recently in semiconductor-grade silicon. The limit of detection for boron in many materials is <10 ng g(-1).
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PMID:Determination of boron in materials by cold neutron prompt gamma-ray activation analysis. 1561 60


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